The diverse radiation types in medical treatments and the natural environment elicit complex biological effects on both cancerous and non-cancerous tissues.Radiation therapy(RT)induces oncological responses,from molec...The diverse radiation types in medical treatments and the natural environment elicit complex biological effects on both cancerous and non-cancerous tissues.Radiation therapy(RT)induces oncological responses,from molecular to phenotypic alterations,while simultaneously exerting toxic effects on healthy tissue.N^(6)-methyladenosine(m^(6)A),a prevalent modification on coding and non-coding RNAs,is a key epigenetic mark established by a set of evolutionarily conserved enzymes.The interplay between m^(6)A modification and radiobiology of cancerous and non-cancerous tissues merits in-depth investigation.This review summarizes the roles of m^(6)A in the biological effects induced by ionizing radiation and ultraviolet(UV)radiation.It begins with an overview of m^(6)A modification and its detection methods,followed by a detailed examination of how m^(6)A dynamically regulates the sensitivity of cancerous tissues to RT,the injury response in non-cancerous tissues,and the toxicological effects of UV exposure.Notably,this review underscores the importance of novel regulatory mechanisms of m^(6)A and their potential clinical applications in identifying epigenetically modulated radiation-associated biomarkers for cancer therapy and estimation of radiation dosages.In conclusion,enzyme-mediated m^(6)A-modification triggers alterations in target gene expression by affecting the metabolism of the modified RNAs,thus modulating progression and radiosensitivity in cancerous tissues,as well as radiation effects on normal tissues.Several promising avenues for future research are further discussed.This review highlights the importance of m^(6)A modification in the context of radiation biology.Targeting epi-transcriptomic molecules might potentially provide a novel strategy for enhancing the radiosensitivity of cancerous tissues and mitigating radiation-induced injury to normal tissues.展开更多
Background:Gastrointestinal(GI)injury is one of the most common side effects of radiotherapy.However,there is no ideal therapy method except for symptomatic treatment in the clinic.Xuebijing(XBJ)is a traditional Chine...Background:Gastrointestinal(GI)injury is one of the most common side effects of radiotherapy.However,there is no ideal therapy method except for symptomatic treatment in the clinic.Xuebijing(XBJ)is a traditional Chinese medicine,used to treat sepsis by injection.In this study,the protective effects of XBJ on radiation-i nduced intestinal injury(RⅢ)and its mechanism were explored.Methods:The effect of XBJ on survival of irradiated C57BL/6 mice was monitored.Histological changes including the number of crypts and the length of villi were evaluated by H&E.The expression of Lgr5^(+)intestinal stem cells(ISCs),Ki67^(+)cells,villin and lysozymes were examined by immunohistochemistry.The expression of cytokines in the intestinal crypt was detected by RT-PCR.DNA damage and apoptosis rates in the small intestine were also evaluated by immunofluorescence.Results:In the present study,XBJ improved the survival rate of the mice after 8.0and 9.0 Gy total body irradiation(TBI).XBJ attenuated structural damage of the small intestine,maintained regenerative ability and promoted proliferation and differentiation of crypt cells,decreased apoptosis rate and reduced DNA damage in the intestine.Elevation of IL-6 and TNF-α was limited,but IL-1,TNF-β and IL-10 levels were increased in XBJ-treated group after irradiation.The expression of Bax and p53 were decreased after XBJ treatment.Conclusions:Taken together,XBJ provides a protective effect on RⅢby inhibiting inflammation and blocking p53-related apoptosis pathway.展开更多
The human microflora is a complex ecosystem composed of diverse microorganisms mainly distributed in the epidermal and mucosal habitats of the entire body,including the mouth,lung,intestines,skin,and vagina.These micr...The human microflora is a complex ecosystem composed of diverse microorganisms mainly distributed in the epidermal and mucosal habitats of the entire body,including the mouth,lung,intestines,skin,and vagina.These microbial communities are involved in many essential functions,such as metabolism,immunity,host nutrition,and diseases.Recent studies have focused on the microbiota associated with cancers,particularly the oral and intestinal microbiota.Radiotherapy,the most effective cytotoxic modality available for solid tumors,contributes to the treatment of cancer patients.Mounting evidence supports that the microbiota plays pivotal roles in the efficacy and prognosis of tumor radiotherapy.Here,we review current research on the microbiota and cancer development,and describe knowledge gaps in the study of radiotherapy and the microbiota.Better understanding of the effects of the microbiome in tumorigenesis and radiotherapy will shed light on future novel prevention and treatment strategies based on modulating the microbiome in cancer patients.展开更多
The use of iodine-125 （L251） in cancer treatment has been shown to relieve patients＇ pain. Consid- ering dorsal root ganglia are critical for neural transmission between the peripheral and central nervous systems, ...The use of iodine-125 （L251） in cancer treatment has been shown to relieve patients＇ pain. Consid- ering dorsal root ganglia are critical for neural transmission between the peripheral and central nervous systems, we assumed that 125I could be implanted into rat dorsal root ganglia to provide relief for neuropathic pain. 125I seeds with different radioactivity （0, 14.8, 29.6 MBq） were im- planted separately through L4-5 and L5-6 intervertebral foramen into the vicinity of the L5 dorsal root ganglion, von Frey hair results demonstrated the mechanical pain threshold was elevated after implanting 125I seeds from the high radioactivity group. Transmission electron microscopy revealed that nuclear membrane shrinkage, nucleolar margination, widespread mitochondrial swelling, partial vacuolization, lysosome increase, and partial endoplasmic reticulum dilation were visible at 1,440 hours in the low radioactivity group and at 336 hours in the high radio- activity group. Abundant nuclear membrane shrinkage, partial fuzzy nuclear membrane and endoplasmic reticulum necrosis were observed at 1,440 hours in the high radioactivity group. No significant difference in combined behavioral scores was detected between preoperation and postoperation in the low and high radioactivity groups. These results suggested that the mechan- ical pain threshold was elevated after implanting 125I seeds without influencing motor functions of the hind limb, although cell injury was present.展开更多
[Objective] This study aimed to evaluate tbe healthy risk of genetically modified （ GM ） soybeans by using a novel approach for functions and safety of food. [ Me^od] Different from traditional evaluation of substan...[Objective] This study aimed to evaluate tbe healthy risk of genetically modified （ GM ） soybeans by using a novel approach for functions and safety of food. [ Me^od] Different from traditional evaluation of substantial equivalence, three great innovations were performed in this study, involving in basic diet, evalu- ation approaches and principle, as well as the clarification of connotation differences between absolute and relative mass of organs. Hence a novel BDI-GS （Bendib Damage Index and General Score） evaluation approach was established and applied in comparative evaluation between RR GM and natural soybeans. Healthy male ICR mice during linear growth were selected; experimental mice were fed with 15% RR GM soybeans and 15% natural soybeans blending maize meal diets, and control mice were fed with single maize meal diet for 13 d; the mice were dissected after collecting blood samples and perfectly obtained nine organs or tissues to re- cord their masses and conduct statistical analyses. [Result] Plenty of matching information was obtained through simple design. The growth performance of treated mice was markedly of individual differences, some mice were thwarted due to regular intake of RR soybeans. Meanwhile, the functions and safety of RR soybeans were markedly lowered in overall nutritional and healthy effects than those of natural soybeans expressed in GS values, and presents some declines in nutrition and health of thymus, pancreas and spermary; especially, it can make thymus immune （P 〈0.05） in markedly lower level than that of natural soybeans. [ Conclusion] Therefore, major troubles and risks of RR soybeans intake are of personal risks in different degrees, in addition, it may increase sub-health and related chronic epi- demics risks, and herein it will presents certain safety issues. The creation of this novel evaluation system provides a simple and available evaluation approach for functions and potential risks revelation of food effects, and will yield far-reaching influences to safety evaluation and healthy development of GM foods, as well as public health.展开更多
Radiation-induced brain injury(RIBI)represents a severe complication of cranial radiotherapy,substantially diminishing patients’quality of life.Unlike conventional brain injuries,RIBI evokes a unique chronic neuroinf...Radiation-induced brain injury(RIBI)represents a severe complication of cranial radiotherapy,substantially diminishing patients’quality of life.Unlike conventional brain injuries,RIBI evokes a unique chronic neuroinflammatory response that notably aggravates neurodegenerative processes.Despite significant progress in understanding the molecular mechanisms related to neuroinflammation,the specific and precise mechanisms that regulate neuroinflammation in RIBI and its associated toxicological effects remain largely unclear.Additionally,targeted neuroprotective strategies for RIBI are currently lacking.In this study,we systematically characterized the pathophysiology of RIBI using zebrafish(larvae/adults)and murine models.We established direct associations between neuronal damage and cognitive-behavioral deficits.Mechanistically,we proposed a ROS-mitochondrialimmune axis.Specifically,radiation-induced ROS lead to mitochondrial dysfunction,resulting in the leakage of mitochondrial DNA into the cytosol.This,in turn,activated the cGAS-STING pathway,thereby driving persistent microglia-mediated neuroinflammation.Furthermore,we engineered a dual-function nanotherapeutic agent,Pep-Cu_(5.4)O@H151.This agent integrates ultrasmall copper-based nanozymes(Cu_(5.4)O)for ROS scavenging and H151(a STING inhibitor)and is conjugated with peptides that can penetrate the blood-brain barrier and target microglia.This nanoplatform exhibited excellent synergistic therapeutic efficacy by simultaneously neutralizing oxidative stress and blocking inflammatory cascades.Our research provided an in-depth analysis of radiation-induced neurotoxicity,clarifying the crucial ROS-mitochondrial-immune axis.Moreover,we have developed a precise therapeutic strategy on the basis of this mechanism.展开更多
Background:The majority of patients with prostate cancer(PCa)exhibit intrinsic resistance to immune checkpoint blockade(ICB)following radiotherapy(RT).This resistance is generally attributed to the limited antigen pre...Background:The majority of patients with prostate cancer(PCa)exhibit intrinsic resistance to immune checkpoint blockade(ICB)following radiotherapy(RT).This resistance is generally attributed to the limited antigen presentation of heterogeneous cells within tumors.Here,we aimed to isolate and characterize these diverse subgroups of tumor post-RT to understand the molecular mechanisms of their resistance to ICB.Methods:Single-cell RNA-sequencing(scRNA-seq)was used to profile senescent cancer cell clusters induced by RT in LNCaP cells.The expression and phosphorylation levels of ataxia telangiectasia and Rad3-related protein(ATR)were assessed by immunohistochemistry in clinical samples from patients with or without RT.Co-immunoprecipitation,mutagenesis,and Western blotting were used to measure the interactions between proteins.Xenograft experiments were performed to assess the tumor immune response in the mice.Results:We identified a subset of PCa cells that exhibited resistance to RT,characterized by a reduced antigen presentation capability,which enhanced their ability to evade immune detection and resist cytotoxic T-lymphocyte-associated protein 4(CTLA-4)blockade.scRNA-seq revealed that the senescent state was a transient phase of PCa cells post-RT,particularly in CTLA-4 blockade treatmentresistant cells.This state was marked by increased cytosolic ATR level.Cytosolic ATR phosphorylated CD86 in its cytosolic domain and enhanced the interaction between CD86 and its E3 ligaseMARCH1 through electrostatic attraction.Depletion or inhibition of Atr increased the sensitivity to immune attack and improved responses to anti-Ctla-4 antibody treatment in a mouse model.Conclusions:Our findings indicate that the activation of cytosolic ATR,which is associated with cellular senescence,impedes the effectiveness of combined RT and ICB treatments.This discovery may provide valuable insights for improving the efficacy of combined RT and ICB therapies in PCa.展开更多
Objective:Hepatitis B X-interacting protein(HBXIP)plays an important role in breast tumorigenesis,tumor growth and metastasis,but its functional contribution in radioresistance remains poorly understood.As radiotherap...Objective:Hepatitis B X-interacting protein(HBXIP)plays an important role in breast tumorigenesis,tumor growth and metastasis,but its functional contribution in radioresistance remains poorly understood.As radiotherapy served as an essential adjuvant treatment,uncovering the role of HBXIP as well as its downstream molecular XIAP in radioresistance could benefit for the development of individual therapy strategy.Methods:Immunohistochemistry of 42 breast cancer tissue samples and Western blot analysis of proteins from MCF-7 and MDA-MB-231 cells exposed to fractioned doses(γ-rays)were used to identify the expression of HBXIP/XIAP in breast cancer.To verify the radioresistance effects and potential mechanism,the cells were treated with designed pCMV and siRNA of targeting genes,and then measured with MTT assay,clonogenic survival assay and flow cytometry.Furthermore,a subcutaneous xenotransplanted tumor model of breast cancer was established in nude mice to validate the radioresistization effect of HBXIP in vivo.Results:HBXIP and XIAP expression levels in breast cancer tissues were positively correlated with chemoradiotherapy resistance of breast cancer.Overexpression of HBXIP could desensitize MCF-7 and MDA-MB-231 cells to irradiation by inhibiting radiation-induced cell apoptosis,and knockdown of HBXIP in these cells had the converse response.Moreover,up-regulation of HBXIP resulted in the increase of XIAP and NF-κB levels in vitro and in vivo,while down-regulation of HBXIP led to the opposite effects.In addition,inhibition of XIAP and NF-κB abrogated the HBXIP overexpression induced radioresistization and increased cell apoptosis(25.8%augment for siRNA XIAP and 28.1%for NF-κB in MDA-MB-231 cells;25.4%augment for siRNA XIAP and 27.2%for NF–κB in MCF-7 cells).Conclusions:HBXIP enhances radioresistance of human breast cancer cells via upregulating XIAP,and targeting the HBXIP–NF–κB-XIAP pathway may be a potentially effective strategy to enhance the efficacy of radiotherapy for human breast cancer.展开更多
基金supported by grants from the National Natural Science Foundation of China(Grant No.82173467 and 82273577)CAMS Innovation Fund for Medical Sciences(Grant Nos.CIFMS,2022-I2M-2-003 and 2021-I2M-1-042).
文摘The diverse radiation types in medical treatments and the natural environment elicit complex biological effects on both cancerous and non-cancerous tissues.Radiation therapy(RT)induces oncological responses,from molecular to phenotypic alterations,while simultaneously exerting toxic effects on healthy tissue.N^(6)-methyladenosine(m^(6)A),a prevalent modification on coding and non-coding RNAs,is a key epigenetic mark established by a set of evolutionarily conserved enzymes.The interplay between m^(6)A modification and radiobiology of cancerous and non-cancerous tissues merits in-depth investigation.This review summarizes the roles of m^(6)A in the biological effects induced by ionizing radiation and ultraviolet(UV)radiation.It begins with an overview of m^(6)A modification and its detection methods,followed by a detailed examination of how m^(6)A dynamically regulates the sensitivity of cancerous tissues to RT,the injury response in non-cancerous tissues,and the toxicological effects of UV exposure.Notably,this review underscores the importance of novel regulatory mechanisms of m^(6)A and their potential clinical applications in identifying epigenetically modulated radiation-associated biomarkers for cancer therapy and estimation of radiation dosages.In conclusion,enzyme-mediated m^(6)A-modification triggers alterations in target gene expression by affecting the metabolism of the modified RNAs,thus modulating progression and radiosensitivity in cancerous tissues,as well as radiation effects on normal tissues.Several promising avenues for future research are further discussed.This review highlights the importance of m^(6)A modification in the context of radiation biology.Targeting epi-transcriptomic molecules might potentially provide a novel strategy for enhancing the radiosensitivity of cancerous tissues and mitigating radiation-induced injury to normal tissues.
基金CAMS Medicine and Health Technology Innovation ProjectGrant/Award Number:2021-I2M-1-060 and 2021-RC310-010+1 种基金National Natural Science Foundation of ChinaGrant/Award Number:81972975。
文摘Background:Gastrointestinal(GI)injury is one of the most common side effects of radiotherapy.However,there is no ideal therapy method except for symptomatic treatment in the clinic.Xuebijing(XBJ)is a traditional Chinese medicine,used to treat sepsis by injection.In this study,the protective effects of XBJ on radiation-i nduced intestinal injury(RⅢ)and its mechanism were explored.Methods:The effect of XBJ on survival of irradiated C57BL/6 mice was monitored.Histological changes including the number of crypts and the length of villi were evaluated by H&E.The expression of Lgr5^(+)intestinal stem cells(ISCs),Ki67^(+)cells,villin and lysozymes were examined by immunohistochemistry.The expression of cytokines in the intestinal crypt was detected by RT-PCR.DNA damage and apoptosis rates in the small intestine were also evaluated by immunofluorescence.Results:In the present study,XBJ improved the survival rate of the mice after 8.0and 9.0 Gy total body irradiation(TBI).XBJ attenuated structural damage of the small intestine,maintained regenerative ability and promoted proliferation and differentiation of crypt cells,decreased apoptosis rate and reduced DNA damage in the intestine.Elevation of IL-6 and TNF-α was limited,but IL-1,TNF-β and IL-10 levels were increased in XBJ-treated group after irradiation.The expression of Bax and p53 were decreased after XBJ treatment.Conclusions:Taken together,XBJ provides a protective effect on RⅢby inhibiting inflammation and blocking p53-related apoptosis pathway.
基金supported by grants from the Science Foundation for Distinguished Young Scholars of Tianjin(Grant No.20JCJQJC00100)the National Natural Science Foundation of China(Grant Nos.81572969,81730086 and 81872555)+1 种基金the Drug Innovation Major Project of China(Grant No.2018ZX09711001-007-008)the PUMC Graduate Innovation Fund(Grant No.2018-1001-04 and 2019-1001-06)。
文摘The human microflora is a complex ecosystem composed of diverse microorganisms mainly distributed in the epidermal and mucosal habitats of the entire body,including the mouth,lung,intestines,skin,and vagina.These microbial communities are involved in many essential functions,such as metabolism,immunity,host nutrition,and diseases.Recent studies have focused on the microbiota associated with cancers,particularly the oral and intestinal microbiota.Radiotherapy,the most effective cytotoxic modality available for solid tumors,contributes to the treatment of cancer patients.Mounting evidence supports that the microbiota plays pivotal roles in the efficacy and prognosis of tumor radiotherapy.Here,we review current research on the microbiota and cancer development,and describe knowledge gaps in the study of radiotherapy and the microbiota.Better understanding of the effects of the microbiome in tumorigenesis and radiotherapy will shed light on future novel prevention and treatment strategies based on modulating the microbiome in cancer patients.
基金supported by Technology Foundation for Selected Overseas Chinese Scholar,Ministry of Personnel of China,2011,Ren 1144
文摘The use of iodine-125 （L251） in cancer treatment has been shown to relieve patients＇ pain. Consid- ering dorsal root ganglia are critical for neural transmission between the peripheral and central nervous systems, we assumed that 125I could be implanted into rat dorsal root ganglia to provide relief for neuropathic pain. 125I seeds with different radioactivity （0, 14.8, 29.6 MBq） were im- planted separately through L4-5 and L5-6 intervertebral foramen into the vicinity of the L5 dorsal root ganglion, von Frey hair results demonstrated the mechanical pain threshold was elevated after implanting 125I seeds from the high radioactivity group. Transmission electron microscopy revealed that nuclear membrane shrinkage, nucleolar margination, widespread mitochondrial swelling, partial vacuolization, lysosome increase, and partial endoplasmic reticulum dilation were visible at 1,440 hours in the low radioactivity group and at 336 hours in the high radio- activity group. Abundant nuclear membrane shrinkage, partial fuzzy nuclear membrane and endoplasmic reticulum necrosis were observed at 1,440 hours in the high radioactivity group. No significant difference in combined behavioral scores was detected between preoperation and postoperation in the low and high radioactivity groups. These results suggested that the mechan- ical pain threshold was elevated after implanting 125I seeds without influencing motor functions of the hind limb, although cell injury was present.
基金Supported by Development Fund of the Institute of Radiation Medicine(No.SF1227)Research Fund for Youth Scholars of Union Medical College(No.2012D03)Research Fund for the Doctoral Program of Higher Education of China(No.20121106120042)
文摘[Objective] This study aimed to evaluate tbe healthy risk of genetically modified （ GM ） soybeans by using a novel approach for functions and safety of food. [ Me^od] Different from traditional evaluation of substantial equivalence, three great innovations were performed in this study, involving in basic diet, evalu- ation approaches and principle, as well as the clarification of connotation differences between absolute and relative mass of organs. Hence a novel BDI-GS （Bendib Damage Index and General Score） evaluation approach was established and applied in comparative evaluation between RR GM and natural soybeans. Healthy male ICR mice during linear growth were selected; experimental mice were fed with 15% RR GM soybeans and 15% natural soybeans blending maize meal diets, and control mice were fed with single maize meal diet for 13 d; the mice were dissected after collecting blood samples and perfectly obtained nine organs or tissues to re- cord their masses and conduct statistical analyses. [Result] Plenty of matching information was obtained through simple design. The growth performance of treated mice was markedly of individual differences, some mice were thwarted due to regular intake of RR soybeans. Meanwhile, the functions and safety of RR soybeans were markedly lowered in overall nutritional and healthy effects than those of natural soybeans expressed in GS values, and presents some declines in nutrition and health of thymus, pancreas and spermary; especially, it can make thymus immune （P 〈0.05） in markedly lower level than that of natural soybeans. [ Conclusion] Therefore, major troubles and risks of RR soybeans intake are of personal risks in different degrees, in addition, it may increase sub-health and related chronic epi- demics risks, and herein it will presents certain safety issues. The creation of this novel evaluation system provides a simple and available evaluation approach for functions and potential risks revelation of food effects, and will yield far-reaching influences to safety evaluation and healthy development of GM foods, as well as public health.
基金supported by the National Natural Science Foundation of China(82273577,82304079)the CAMS Innovation Fund for Medical Sciences(2023-I2M-3-018,2023-I2M-2-008,2021-I2M-1-042)+2 种基金the Natural Science Foundation of Tianjin Municipal Science and Technology Commission(23JCJQJC00230,24JCZDJC00580)the Fundamental Research Funds for the Central Universities(3332023066,3332024079)Fujian Research and Training Grants for Young and Middle-aged Leaders in Healthcare.
文摘Radiation-induced brain injury(RIBI)represents a severe complication of cranial radiotherapy,substantially diminishing patients’quality of life.Unlike conventional brain injuries,RIBI evokes a unique chronic neuroinflammatory response that notably aggravates neurodegenerative processes.Despite significant progress in understanding the molecular mechanisms related to neuroinflammation,the specific and precise mechanisms that regulate neuroinflammation in RIBI and its associated toxicological effects remain largely unclear.Additionally,targeted neuroprotective strategies for RIBI are currently lacking.In this study,we systematically characterized the pathophysiology of RIBI using zebrafish(larvae/adults)and murine models.We established direct associations between neuronal damage and cognitive-behavioral deficits.Mechanistically,we proposed a ROS-mitochondrialimmune axis.Specifically,radiation-induced ROS lead to mitochondrial dysfunction,resulting in the leakage of mitochondrial DNA into the cytosol.This,in turn,activated the cGAS-STING pathway,thereby driving persistent microglia-mediated neuroinflammation.Furthermore,we engineered a dual-function nanotherapeutic agent,Pep-Cu_(5.4)O@H151.This agent integrates ultrasmall copper-based nanozymes(Cu_(5.4)O)for ROS scavenging and H151(a STING inhibitor)and is conjugated with peptides that can penetrate the blood-brain barrier and target microglia.This nanoplatform exhibited excellent synergistic therapeutic efficacy by simultaneously neutralizing oxidative stress and blocking inflammatory cascades.Our research provided an in-depth analysis of radiation-induced neurotoxicity,clarifying the crucial ROS-mitochondrial-immune axis.Moreover,we have developed a precise therapeutic strategy on the basis of this mechanism.
基金Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences,Grant/Award Number:2021-RC310-010National Natural Science Foundation of China,Grant/Award Numbers:81972654,81730086+1 种基金CAMS Innovation Fund for Medical Sciences,Grant/Award Numbers:2021-I2M-1-042,2021-I2M-1-060Tianjin International Student Science and Technology Activities,Grant/Award Number:20160014。
文摘Background:The majority of patients with prostate cancer(PCa)exhibit intrinsic resistance to immune checkpoint blockade(ICB)following radiotherapy(RT).This resistance is generally attributed to the limited antigen presentation of heterogeneous cells within tumors.Here,we aimed to isolate and characterize these diverse subgroups of tumor post-RT to understand the molecular mechanisms of their resistance to ICB.Methods:Single-cell RNA-sequencing(scRNA-seq)was used to profile senescent cancer cell clusters induced by RT in LNCaP cells.The expression and phosphorylation levels of ataxia telangiectasia and Rad3-related protein(ATR)were assessed by immunohistochemistry in clinical samples from patients with or without RT.Co-immunoprecipitation,mutagenesis,and Western blotting were used to measure the interactions between proteins.Xenograft experiments were performed to assess the tumor immune response in the mice.Results:We identified a subset of PCa cells that exhibited resistance to RT,characterized by a reduced antigen presentation capability,which enhanced their ability to evade immune detection and resist cytotoxic T-lymphocyte-associated protein 4(CTLA-4)blockade.scRNA-seq revealed that the senescent state was a transient phase of PCa cells post-RT,particularly in CTLA-4 blockade treatmentresistant cells.This state was marked by increased cytosolic ATR level.Cytosolic ATR phosphorylated CD86 in its cytosolic domain and enhanced the interaction between CD86 and its E3 ligaseMARCH1 through electrostatic attraction.Depletion or inhibition of Atr increased the sensitivity to immune attack and improved responses to anti-Ctla-4 antibody treatment in a mouse model.Conclusions:Our findings indicate that the activation of cytosolic ATR,which is associated with cellular senescence,impedes the effectiveness of combined RT and ICB treatments.This discovery may provide valuable insights for improving the efficacy of combined RT and ICB therapies in PCa.
基金National Natural Science Foundation of China（81071906, 81172127, 81572969） U.S. National Center of Complementary and Ahemative Medicine（NCCAM, R01AT005076） U.S. National Institute of General Medical Sciences （NIGMS, R01GM063075）
基金This study was supported by the grants from the National Natural Science Foundation of China (No.31770910 and No.81730086).
文摘Objective:Hepatitis B X-interacting protein(HBXIP)plays an important role in breast tumorigenesis,tumor growth and metastasis,but its functional contribution in radioresistance remains poorly understood.As radiotherapy served as an essential adjuvant treatment,uncovering the role of HBXIP as well as its downstream molecular XIAP in radioresistance could benefit for the development of individual therapy strategy.Methods:Immunohistochemistry of 42 breast cancer tissue samples and Western blot analysis of proteins from MCF-7 and MDA-MB-231 cells exposed to fractioned doses(γ-rays)were used to identify the expression of HBXIP/XIAP in breast cancer.To verify the radioresistance effects and potential mechanism,the cells were treated with designed pCMV and siRNA of targeting genes,and then measured with MTT assay,clonogenic survival assay and flow cytometry.Furthermore,a subcutaneous xenotransplanted tumor model of breast cancer was established in nude mice to validate the radioresistization effect of HBXIP in vivo.Results:HBXIP and XIAP expression levels in breast cancer tissues were positively correlated with chemoradiotherapy resistance of breast cancer.Overexpression of HBXIP could desensitize MCF-7 and MDA-MB-231 cells to irradiation by inhibiting radiation-induced cell apoptosis,and knockdown of HBXIP in these cells had the converse response.Moreover,up-regulation of HBXIP resulted in the increase of XIAP and NF-κB levels in vitro and in vivo,while down-regulation of HBXIP led to the opposite effects.In addition,inhibition of XIAP and NF-κB abrogated the HBXIP overexpression induced radioresistization and increased cell apoptosis(25.8%augment for siRNA XIAP and 28.1%for NF-κB in MDA-MB-231 cells;25.4%augment for siRNA XIAP and 27.2%for NF–κB in MCF-7 cells).Conclusions:HBXIP enhances radioresistance of human breast cancer cells via upregulating XIAP,and targeting the HBXIP–NF–κB-XIAP pathway may be a potentially effective strategy to enhance the efficacy of radiotherapy for human breast cancer.
基金National Natural Science Foundation of China（81071906, 81172127, 81572969, 81402633） Technology and Development and Research Projects for Research Institutes, Ministry of Science and Technology（2014EG150134）+3 种基金 Tianjin Science ＆ Technology Pillar Program（14ZCZDSY00001） Natural Science Foundation of Tianjin（16JCQNJC13600） Peking Union Medical College Youth Innovation Fund（1581） IRM-CAMS Research Fund（1614）
基金National Natural Science Foundation of China（81071906, 81172127, 81572969） Ministry of Science and Technology Researth Institutes Development Project（2014EG150134）+3 种基金 Technology and Development and Research Projects for Research Institutes, Ministry of Science and Technology（2014EG150134） Tianjin Science and Technology Support Plan Project（14ZCZDSY00001） PUMC Youth Fund, the Fundamental Research Funds for the Central Universities（33320140187） Institute of Radiation Medicine, Chinese Academy of Medical Sciences Research Fund （1547,1522）.
